Autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, result from aberrant immune responses to normal self antigens. Although much work has been done to describe the pathologic characteristics of these syndromes, significantly less is known about the pathogenesis of the illnesses. The central mechanism in these diseases is felt to be a loss of tolerance--due to either failure of thymic selection or loss of peripheral tolerance--with the subsequent expansion of effector cells which recognize and respond to self antigens. We have developed a mouse model of self-reactivity in which thymic positive selection occurs in the absence of negative selection. These transgenic animals (K14 mice) express MHC class II (I-A) molecules on thymic cortical epithelium only: neither thymic medullary epithelium nor peripheral antigen presenting cells are I-A- positive. Postive selection of CD4=T cells does occur in the K14 thymus; however, superantigen-mediated negative selection does not. The K14 CD4 cells are autoreactive as they proliferate extensively to and specifically lyse I-A-positive cells. We propose to utilize the K14 mouse to investigate the mechanisms of thymic selection and peripheral activation which lead to autoreactivity. In Aim 1, we will examine the MHC class II and tissue specificity of thymic selection by examining the response of self-reactive K14 CD4 cells to select populations of thymic and peripheral antigen presenting cells (APCs). In Aim 2, we will use adoptive transfer and skin grafting to ask if the self-reactive cells present in the K14 mice are activated in vivo in the presence of MHC class II-positive APCs and if that activation leads to an autoimmune response and pathology. In Aim 3, K14 mice will be exposed to syngeneic MHC class II-positive APCs through both intravenous and oral regimens and the response to self-MHC re- examined both in vitro and in vivo. Thus, the K14 mice offer a model to understand the development of autoreactive cells and possible treatments of autoimmune diseases.